snip...
Carlton:
>>Also, TNF is able to bind the tar element of the LTR when no tat
>>is present, and initiate transcription. This was an unfortunate
>>side effect noted by F. Wong-Staahl when she was testing anti-tat
>>compounds. She was able to reduce tat concentrations nearly to zero,
>>but replication still occurred in the presence of TNF
Carlton: Is it actually the TNF or does TNF stimulate release of
NF-kB which binds and initiates transcription? I forget.
snip
dhavilan at IMM2.IMM.UTH.TMC.EDU ("David L. Haviland, Ph.D.") wrote:
>I do recall an old (about 1992) conversation with a group of other
>immunologist, some of which were T-cell "folk". I recall the conversation
>centering around a clinical study where HIV infected patients were given
>TNF to "hopefully" reduce the kaposi sarcomas. I don't recall the number
>of patients involved with the study but I recall hearing that all TNF
>treated patients quickly progressed to full blown AIDS and dying shortly
>thereafter. It was a somber "hindsight" discussion where it was mentioned
>that a few months after this study, TNF was found to bind to tat(?) and
>initiated viral transcription.
>Can anyone shed anymore light on this for me?
You're correct and this is what I was alluding to earlier. The KS
study was only 5 people but all suffered increased numbers of lesions
(see J. AIDS 1989;2(1):54-58). Aside from this study, there are
numerous ancillary studies supporting the role of pathologically
increased levels of TNF playing a role both in advancing KS as well as
HIV (see, e.g., JID, 1994;169:420-4 or J of Imm,
1992;149(11):3727-34)..
Indeed, the reason for the renewed interest in thalidomide is that it
reduces TNF levels. I think there's probably MUCH better/safer ways
to do that, specifically by using carnitine (see work of de Simone et
al.) Or if a drug is the only thing that will satisfy (grr) Ketotifen
might be a reasonable alternative.
But I find carnitine particularly attractive since people with normal
levels of TNF had no further reduction. By contrast, studies of the
angiogenesis inhibitor pentoxifylline flopped partially because when
people's normal level plummeted, more rapid progression ensued (see
Blood, 1991;77(8):1653-6). I mean, TNF is there for a reason, one
doesn't want to wipe it out.
George M. Carter
Other problematic cytokines, at least re KS, are oncostatin M and
IL-6.
George M. Carter
